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Metabotropic glutamate receptors on peripheral sensory neuron terminals as targets for the development of novel analgesics

Molecular Psychiatry volume 6, pages 615–617 (2001)Cite this article

The amino acid glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. Glutamate activates ionotropic glutamate receptors (iGluRs) which include the NMDA, AMPA and kainate receptors, and the metabotropic glutamate receptors (mGluRs) which are coupled to G proteins. To date, eight mGluR subtypes have been cloned and are termed mGluRs 1–8. These are broadly classified into group I (mGluRs 1 and 5), II (mGluRs 2 and 3) and III (mGluRs 4, 6, 7 and 8), based on their sequence homology, agonist pharmacology and coupling to intracellular effector systems.1

While the function of glutamate and glutamate receptors in the CNS has been studied in great detail, the importance of these receptors in the peripheral nervous system has only recently been acknowledged. A growing body of evidence indicates that glutamate levels rise in peripheral tissues in response to inflammation. Increases in glutamate levels in the skin have been found in response to inflammatory agents such as intraplantar formalin.2 Electrical stimulation of the sciatic nerve results in a significant increase in glutamate release in the hind paw of rats.3 Interestingly, stimulation of the sciatic nerve by a selective C fiber activator, capsaicin, also results in glutamate release in the rat hind paw,3 suggesting that nociceptive-specific primary afferent fibers are a source of peripheral glutamate. Evidence for physiological relevance of this peripheral glutamate was obtained when intraplantar injection of glutamate caused increased thermal and mechanical sensitivity in rats and mice.4,5,6 The potential clinical importance of elevated glutamate levels in the periphery is supported by the finding that glutamate levels are markedly elevated in synovial fluid from knee joints of arthritis patients.7 These findings suggest an important role for glutamate as a peripheral inflammatory pain mediator, and that inhibitors of glutamate release, glutamate receptors, or inhibitors of intracellular glutamate-activated pathways may harbor important therapeutic potential.

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  1. Division of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, 77030, TX, USA

    F Karim, G Bhave & R W Gereau IV

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  1. F Karim
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Correspondence to R W Gereau IV.

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Karim, F., Bhave, G. & Gereau IV, R. Metabotropic glutamate receptors on peripheral sensory neuron terminals as targets for the development of novel analgesics. Mol Psychiatry 6, 615–617 (2001). https://doi.org/10.1038/sj.mp.4000961

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